PROJECT SUMMARY Poorly healing wounds linked to age or diabetes have an annual health care cost of over $25 billion. Current therapies consist of application of recombinant growth factors to stimulate angiogenesis and provisional matrix synthesis, but this approach has had limited effectiveness and is very costly. Thus new approaches to correct both inadequate angiogenesis and the prolonged inflammatory phase of poorly healing wounds are needed. My laboratory has been studying the role of Homeobox (Hox) genes in pathological tissue remodeling and have identified a group of Hox3 genes (HoxA3,B3 and D3) whose expression is upregulated during normal tissue repair but not in compromised diabetic wounds. We developed a topical gene transfer methods to deliver plasmids expressing HoxD3 and HoxA3 and observed significant improvement in healing of diabetic wounds. More recently we observed that that paralogous HoxB3 is the most potent and can improve healing to rates indistinguishable from healthy mice. Our preliminary evidence indicates that along with stimulating angiogenesis, HoxB3 also corrects the prolonged inflammatory phase of poorly healing wounds and promotes influx of immune suppressive late wound macrophages and mast cells. Thus restoring of HoxB3 reprograms poorly healing wounds to allow them to transition from a prolonged inflammatory state to an immunosuppressive state that is conducive to wound resolution. We have also observed changes in a number of other immune cells in diabeetic wounds that are corrected by HoxB3 but the role of these cells has not yet been explored. Thus we propose to conduct studies to identify downstream mediators of HoxB3 and establish the functional roles of changes in immune cell trafficking induced by HoxB3 that contribute to greatly improved wound repair.